Variant chr8-100924955-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate

The NM_145690.3(YWHAZ):c.379C>T(p.Arg127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

YWHAZ
NM_145690.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.30

Variant links:

Genes affected

YWHAZ (HGNC:12855): (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta) This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 99% identical to the mouse, rat and sheep orthologs. The encoded protein interacts with IRS1 protein, suggesting a role in regulating insulin sensitivity. Several transcript variants that differ in the 5' UTR but that encode the same protein have been identified for this gene. [provided by RefSeq, Oct 2008]

YWHAZ links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a chain 14-3-3 protein zeta/delta (size 244) in uniprot entity 1433Z_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_145690.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), YWHAZ. . Gene score misZ 3.0961 (greater than the threshold 3.09). Trascript score misZ 4.4099 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

PP5

Variant 8-100924955-G-A is Pathogenic according to our data. Variant chr8-100924955-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3342334.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YWHAZ	NM_145690.3 linkuse as main transcript	c.379C>T	p.Arg127Cys	missense_variant	3/6	ENST00000395958.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YWHAZ	ENST00000395958.6 linkuse as main transcript	c.379C>T	p.Arg127Cys	missense_variant	3/6	1	NM_145690.3	P1	P63104-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 07, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35982160, 35982159) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;T;T;T;T;.;T;T;T;T;T;T;T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

.;D;.;.;.;D;.;D;.;D;.;.;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

3.9

H;H;H;H;H;.;.;.;H;.;H;H;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-6.8

D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0

D;D;D;D;D;.;.;.;D;.;D;D;.;.

Vest4

0.92

MutPred

0.95

Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);.;.;.;Gain of ubiquitination at K122 (P = 0.0625);.;Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);Gain of ubiquitination at K122 (P = 0.0625);

MVP

0.98

MPC

2.2

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over